It is estimated that 24.3 million people have dementia today, with 4.6 million additional cases of dementia occurring every year (one new case every 7 seconds) (Ferri et al., “Global Prevalence of Dementia: A Delphi Consensus Study,” Lancet 366:2112-2117 (2005)). The numbers of people affected worldwide are expected to double every 20 years to reach 81.1 million by 2040 (Ferri et al., “Global Prevalence of Dementia: A Delphi Consensus Study,” Lancet 366:2112-2117 (2005)). An estimated 4.5 million Americans had Alzheimer's Disease in 2000 (Hebert et al., “Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census,” Archives of Neurology 60:1119-1122 (2003)). The number of Americans with Alzheimer's has more than doubled since 1980 (Hebert et al., “Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census,” Archives of Neurology 60:1119-1122 (2003)) and will continue to grow; by 2050 the number of individuals with Alzheimer's is expected to be more than 11.3 million in the US alone (Hebert et al., “Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census,” Archives of Neurology 60:1119-1122 (2003)). From the time of diagnosis, people with Alzheimer's Disease survive about half as long as those of similar age without dementia (Larson et al., “Survival After Initial Diagnosis of Alzheimer Disease,” Annals of Internal Medicine, 501-509 (2004)). The average survival time is affected by the age at diagnosis and the severity of other medical conditions (Larson et al., “Survival After Initial Diagnosis of Alzheimer Disease,” Annals of Internal Medicine, 501-509 (2004)). National direct and indirect annual costs of caring for individuals with Alzheimer's Disease are at least U.S. $100 billion (Ernst et al., “The U.S. Economic and Social Costs of Alzheimer's Disease Revisited,” Am. J. Public Health 84:1261-1264 (1994)).
Alzheimer's Disease is an age-related neurodegenerative disorder that is characterized by progressive loss of memory and deterioration of higher cognitive function (Kar et al., “Interactions Between β-Amyloid and Central Cholinergic Neurons: Implications for Alzheimer's Disease,” J. Psychiatry Neurosci. 29:427-441 (2004)). Alzheimer's Disease is not a normal part of aging. The brain of an individual with the disease exhibits extracellular plaques and intracellular neurofibrillary tangles. The extracellular plaques consist of aggregates of 39-42 amino-acid peptides known as β-amyloid peptides (Aβ) (Selkoe, D. J. “Cell Biology of Protein Misfolding: The Examples of Alzheimer's and Parkinson's Diseases,” Nat. Cell Biol. 6:1054-1061 (2004)). The Aβ peptides are formed by enzyme-(β-secretase) catalyzed degradation of transmembrane proteins of unknown function called Amyloid Precursor Proteins (APP) (Saido et al., “Metabolism of Amyloid β Peptide and Pathogenesis of Alzheimer's Disease. Toward Presymptomatic Diagnosis, Prevention and Therapy,” Neurosci. Res. 54:235-253 (2006)). The aggregated Aβ peptides in plaques exert toxic effects on a wide variety of cells in the nervous system. Neurofibrillary tangles are formed intracellularly in the neuron cell bodies. These tangles consist of intracellular aggregates of hyperphosphorylated tau-protein (Grundke-Iqbal et al., “Abnormal Phosphorylation of the Microtubule-Associated Protein τ (tau) in Alzheimer Cytoskeletal Pathology,” Proc. Natl. Acad. Sci. USA 83:4913-4917 (1986)). Tau (τ) protein is a microtubule-associated protein important for the neuron cytoskeleton.
Currently, only a handful of agents are approved by the Food and Drug Administration for treatment of Alzheimer's Disease. These agents mainly target the synthesis, release, or degradation of neurotransmitters in the cholinergic system; but have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on the progression of the disease. Finding a treatment that delays the onset of Alzheimer's by five years could reduce the number of individuals with Alzheimer's Disease by nearly 50 percent after 50 years (Brookmeyer et al., “Projections of Alzheimer's Disease in the United States and the Public Health Impact of Delaying Disease Onset,” Am. J. Public Health 88:1337-1342 (1998)). There is a need for new Alzheimer's Disease therapeutics.
The present invention is directed to overcoming these and other deficiencies in the art.